Preparation of 16-oxo-isomorphinan



United States Patent ()fiice 3,068,234 Patented Dec. 11, 1962 3,063,234 PREPARATION or 16-0X0-1SOMORPH1NAN Horace D. Brown, Piainfield, N.J., assignor to Merck &.

This invention is concerned generally with novel processes for the preparation of N-substituted-isomorphinan compounds. More particularly, it relates to an improved procedure for the conversion of l6-oxoisomorphinan compounds to the corresponding N-substitilted-isomorphinan compound wherein the substituent attached to the nitrogen atom is a lower aliphatic hydrocarbon radical. These N-substituted-isomorphinan compounds possess analgesic and antitussive activity and are also valuable in the synthesis of morphine and its substitution products.

This application is a continuation of copending application Serial No. 622,815, filed November 19, 1956, which in turn is a continuation of Serial No. 404,128, filed January 14, 1954, both now abandoned.

The N-substituted-isomorphinan compounds obtained in accordance with the process of this invention, which can have, in addition to the lower aliphatic hydrocarbon radical attached to the nitrogen atom, a lower alkyl group attached ot the C-7 carbon atom, a hydroxy radical attached to the C- carbon atom, and/or an unsaturated linkage connecting the C-6 and C7 carbon atoms,- may be chemically represented as follows:

wherein R is an aliphatic hydrocarbon radical containing up to six carbon atoms, R is hydrogen or hydroxy, and R is hydrogen or alkyl.

In accordance with the present invention, a 16-oxoisomorphinan compound (Compound 1 hereinbelow) is reactedwith an aliphatic iodide containing up to six carbon atoms to form the corresponding N-substituted-l6- oxo-isomorphinan compound (Compound 2), and the latter compound is reacted with a reducing agent to produce the corresponding N-substituted-isomorphinan compound (Compound 3). r

The reactions indicated hereinabove may be chemically represented as follows:

wherein R, R and R have the significance above-defined, and R is hydrogen or keto.

The lo-oxo-isomorphinan compounds which may be employed as starting materials in thisnew process include l6-oXo-is0rnorphinans containing a single bond connecting the C6 and C-7 carbon atoms, as for example, 1 6-oxo-isomorphinan, 7-alkyl-16oxo-isomorphinans such as 7-methyl-16-oxo-isomorphinan, 7-ethyl-l6- oxo-isomorphinan, 7-butyl-l6-oxo-isomorphinan, 7-hexyl- Moro-isomorphinan, 10,l-dioxo-isomorphinan, 7-alkyl- 10,l6-dioxo-isomorphinans such as 7-methyl-10,16-dioxoisomorphinan, 7-ethyl-10,I6-dioxo-isomorphinan, 7-propyl 10,16-dioxo-isomorphinan, 7-amyl-10,16-dioxo isomorphinan and also include l-oxo-isomorphinan compounds containing a double bond connecting the C-6 and C-7 carbon atoms as, for example, A -dehydro-16-oxoisomorphinan, A -dehydrQ-IO,16-dioxo-isomorphinan, A dehydro-7-alkyl-l6-oxo-isomorphinans such as A -dehydro-7-methyl-16-oxo-isomorphinan, A -dehydro-7 ethyl- 16-oxo-isomorphinan, A -dehydro-7-propyl-16-oxo isomorphinan, A -dehydro-7-hexyl-16-0xo-isomorphinan, A dehydro-7-methyl-10,16-dioxo-isomorphinan, A -dehydro- 7 ethyl-10,16-diox0-isomorphinan, A -dehydro-7-butyl- 10,16 dioxo-isomorphinan, A -dehydro-7-amyl-10,16-dioxo-isomorphinan and the like.

The reaction between the lfi-oxo-isomo-rphinan compound and the lower aliphatic iodide is ordinarily carried out by bringing the reactants together in the presence of a strong base as, for example, an alkali metal hydride such as sodium hydride, lithium hydride, an alkali metal alkoxide such as sodium alkoxide, an alkali metal per so such as metallic sodium and the like. The reaction is conveniently conducted by allowing the 16-oxo-isomorphinan compound to react with the strong base in an inert organic solvent for a short period of time, and then adding the lower aliphatic iodide to the reaction mixture thereby effecting the introduction of the aliphatic radical into the N-position of the molecule. It is preferred to utilize methyl iodide in order to obtain N-methyl compounds, but other aliphatic hydrocarbon groups such as ethyl, isobutyl, allyl, propyl, hexyl and the like may be introduced in like manner. A slight molar excess of strong base and lower aliphatic iodide is generally employed during this reaction in order to obtain maximum yields of the desired product. As solvent for the reaction, it is preferred to employ dioxane although other inert solvents as, for example, hydrocarbon solvents such as toluene and benzene, dialkyl ethers such as diethyl ether, and the like may be used if desired.

In accordance with this procedure, there is obtained the corresponding l6-oxo-isomorphinan compounds having attached to the nitrogen atom a lower aliphatic hydrocarbon radical as, for example, N-methyl-l6-oxo-isomorphinan, N-ethyl-l6-oxo-isomorphinan, N-isobutyl-l6- oxo-isomorphinan, N-allyl-16-oxo-isomorphinan, N-methyl 10,16-dioXo-isomorphinan, N-ethyl-10,.l6-dioxo-isomorphinan, N-propyl-IO,16-dioxo-isornorphinan, N-isobutyl 10,16 dioxo isomorphinan, N allyl 10,16- dioxo isomorphinan, 7 alkyl 16 oxo isomorphin? an compounds having a lower aliphatic hydrocarbon radical attached to the nitrogen atom such as N,7-dimethyl-16-oxo-isomorphinan, N,7-diethyl-ld-oxo-isomorphinan, N-methyl-7-hexyl-lo-oxo-isomorphinan, N,7-dimethyl-10,16-dioxo-isomorphinan, N,7-diethyl-10,16 dioxo isomorphinan, N-butyl-7-isopropyl-l0,16-dioxo-isomorphinan, N-methyl-7-hexyl-10,16-dioxo-isomorphinau as well as the corresponding M-dehydro-lfi-oxo-isomorphinan compounds having a lower aliphatic hydrocarbon radical attached to the nitrogen atom such as A -dehydro- N-methyl-16-oxo-isomorphinan, A -dehydro-N-ethyl116- oxo isomorphinan, u -dehydro-N-allyhl6-oxo-isomore phinan, A -dehydrO-N-methyI-IO,l6-dioXo-isomorphinan, A -dehydro-N-ethyldO,16-dioxo-isomorphinan, A -dehydro-N-allyl-IO,16-dioxo-isomorphinan, A -dehydro N,7- dimethyl-l6-oXo-isomorphinan, A -dehydro-N,7-diethyllo-oxo-isomorphinan, A -dehydro-N-allyl-7-methyl 16- oxo-isomorphinan, A dehydro-N,7-dimethyl-10,16-dioxo-isomorphinan, A dehydro-N,7-diethyl-l0,16-dioxoisomorphinan, A dehydro-N-allyl-7-methyl-l0,16-dioxo aoeaesa isomorphinan and the like. The resulting 16-oxo-isomorphinan compound having a lower aliphatic hydrocarbon radical attached to the nitrogen atom is conveniently isolated from the reaction mixture by decomposing the reaction complex with water, separating the aqueous layer containing the alkali metal iodide, and evaporating the organic solvent extract. The residual N-snbstituted-16- oxo-isomorphinan compound is ordinarily obtained as an oil which crystallizes slowly on standing and can be purified further if desired by recrystallization from organic solvents such as ether, but this material can be used, without further purification, in the subsequent reduction operation of the presently invented combination procedure.

The N-substituted-l6-oxo-isomorphinan compound is then reacted with a reducing agent to produce the corresponding N-substituted-isomorphinan compound. The reducing agents which are ordinarily employed in this procedure include the alkali metal aluminum hydrides such as lithium aluminum hydride, hydrogen in the presence of a hydrogenation catalyst and the like. When utilizing an alkali metal aluminum hydride, it is ordinarily prefered to employ an excess of the reducing agent and to carry out the reduction by heating the N-substituted-16-oxo-ismorphinan compound and the alkali metal aluminum hydride in solvents such as ether or dioxane at the reflux temperature of the solvent for a period of about eight to fifteen hours. In accordance with this procedure and utilizing the aforementioned intermediate N-substituted-l6-oxo-isomorphinan compounds having a single bond connecting the (3-6 and C-7 canbon atoms there are obtained the corresponding r-substituted-isomorphinan compounds as, for example, N-methyl-isomorphinan, N-ethyl-isomorphinan, N-allylisomorphinan, and the like. Where the inetrmediate N-substituted-lisomorphinan compound also contains a 10-oxo-substituent, there are obtained the corresponding N-substituted- 10-hydroxy-isomorphinan compounds as, for example, Nmethyl-10-hydroxy-isomorphinan, N-ethyl-lO-hydroxyisomorphinan, N-allyl-IO-hydroxy-isomorphinan, and the like. Where the intermediate N-substituted-l-oxo-isomorphinan intermediate contains a 7-alkyl sustituent, there are obtained the corresponding N-substi-tuted-7- alkyl-isornorphinan compounds such as N,7-dimethylisomorphinan, N,7 diethyl-isomorphinan, N allyl 7- methyl-isomorphinan, N,7 dimethyl-ltl-hydroxy-isomorphinan, N,7-diethyl-10-hydroxy-isomorphinan, N-allyl-7- methyl-10-hydroxy-isomorphinan, and the like. Where the intermediate N-substituted-l6-oxo-isomorphinan compound possesses a double bond connecting the C-6 and 'C-7 carbon atoms, there is obtained upon reaction with the alkali metal aluminum hydride the corresponding A -dehydro-N-substituted-isomorphinan compound, as for example, A -dehydro-N-methyl-isomorphin-an, A -dehydro-N-ethyl-isomorphinan, A -dehydro N allyl-isomorphian, A -dehydro-N,7-dimethyl-isomorphinan, A dehydro-N,7-diethyl-isomorphinan, A dehydro N allyl-7- methyLisomor hinan, A -dehydro-N-isobutyl-7-hexyl-isomorpih-inan, A -dehydro N methyl-10-hydroxy-isomorphinan, A dehydro-N-ethyl-IO-hydroxy isomorphinan, A dehydro-N-allyl-10-hydroxy-isomorphinan, A dehydro-N,7-dimethyl-IO-hydroxy-isomorphinan, A -dehydro- N,7 diethyl-10-hydroxy-isomorphirran, A -dehydro-N-allyl-7-methyl 10* hydroxy isomorphian, A -dehydro-N- amyl-7-isopropyl-10-hydroxy-isomorphinan and the like.

These A -dehydrodsomorphinan compounds having an aliphatic hydrocarbon radical attached to the nitrogen atom can be reduced to the corresponding N-substitutedisomorphinan compound in which a Single bond connects the C-6 and C-7 carbon atoms by reacting said A -dehydro-N-substituted-isomorphinan compound with hydrogen in the presence of a hydrogenation catalyst such as platinum, platinum oxide, palladium, Raney nickel and the like. Alternatively, instead of utilizing an alkali metal aluminum hydride in the reaction with the intermediate A -dehydro N substituted 16-oxo-isomorphinan compound, I can employ hydrogen in conjunction with a hydrogenation catalyst such as copper chromite whereby the unsaturated linkage connecting the C6 and C7 carbon atoms is reduced simultaneously with the 16- oxo-substituent thereby forming the corresponding N-substituted-isomorphinan compound directly.

The N-substituted-isomorphinan compound is conveniently isolated by adding water to the reduction mixture, separating the aqueous extract, and evaporating the organic layer to dryness. The residual N-substituted-isomorphinan compound is ordinarily obtained in the form of an oil which is conveniently purified by conversion to appropriate acid addition salts.

The following examples illustrate methods of carrying out the present invention but it is to be understood that those examples are given for purposes of illustration and not of limitation.

Example 1 To 2.00 g. (0.084 mole) of A -dehydro-16-oxo-isomorphinan dissolved in ml. of dry toluene, a dry toluene suspension of 0.21 g. (5% excess) of sodium hydride was added and the mixture stirred and heated at reflux temperature of the solvent for two hours. To the yellow solution 0.75 ml. of methyl iodide was added dropwise and the heating was continued at reflux temperature for an additional two hours. The solution was then cooled, treated cautiously with a small volume of water, and finally washed with water to remove the precipitated sodium iodide. The organic layer was concentrated in vacuo leaving a straw-colored oil, highly soluble in benzene, ether, and alcohol. Crystallization from ethcf' yielded a solid product, M.P. 117 C. In contrast there to, the starting material is a solid, M.P. 237 C., only slightly soluble in alcohol and benzene.

Without further purification the A -dehydro-N-methyl-l6-0Xo-isomorphinan was dissolved in 100 ml. of puri fied dioxane and the solution was brought to reflux temperature. An ether solution of 1 g. of lithium aluminum hydride was added dropwise, most of the ether was distilled off, and the remaining solution refluxed overnight. Decomposition of the solution with a minimum volume of water, filtration, and distillation of the solvent yielded a residual oil. A solution of hydrogen bromide in ether was added to the oil to obtain the crude solid hydrobromide salt of A -dehydro-N-methyl-isomorphinan. Recrystallization of the hydrobromide from alcohol-ether yielded an essentially pure product, M.P. 242-243 C. Analysis.-Calcd for c qHzzNBl' (320.28) C, 63.75; H, 6.92; N, 4.37. Found: C, 63.90; H, 6.94; N, 4.14.

Example 2 Two grams of A -dehydro-10,16-dioxo-isomorphinan was reacted in boiling dioxane with 0.19 g. of sodium hydride as described in Example 1. After two hours at reflux temperature, the yellow solution was treated with 4.49 cc. of methyl iodide and the mixture refluxed for an additional two hours. Decomposition of th e complex with water and concentration of the organic solvent. phase in vacuo gave an oil which was dried by dissolution in benzene and subsequent removal of the benzene. To a refluxing dioxane solution of this dry oil, which was essentially M-dehydro-N-methyl-IO,l6-dioxo-isomorphinan, was added an ether solution of 0.5 g. of lithium aluminum hydride. After distillation of the ether the solution was refluxed three hours. Isolation, as described above, gave an oil which was converted directly to a hydrobromide salt of A -dehydro-l0-hydroxy-N-methylisomorphinan. Analysis. Calcd for C1'1H21ONB1 (335.27) C, 60.80; H, 6.31; N, 4.18. Found: C, 60.70; H, 6.48; N, 3.94.

Example 3 A -dehydro 7 methyl-16-oxo-isomorphinan (0.85 g.) and sodium hydride (0.1 g.) were reacted together for -viscous oil.

three hours in purified dioxane at reflux temperature. Methyl iodide (0.2 ml.) was added and the refluxing continued for an additional hour. Decomposition with water and concentration in vacuo to remove the dioxane was followed by benzene extraction, washing to remove sodium iodide, and distillation of the solvent to yield a dry, Recrystallization of the benzene-petroleum ether yielded substantially pure A -dehydro-Nfl-dime-thyl- 16-oxo-isomorphinan, 159-l61 C. Analysis.--Calcd.

for CgH ON (267.36) C, 80.85; H, 7.92. Found: C, 80.13; H, 7.85.

To 100 ml. of boiling dioxane containing 0.25 g. of the A -dehydro-NJ-dimethyl-I6-oxo-isorrrorphinan produced above, about 0.59 'g. of lithium aluminum hydride was added and the reduction carried out as described in the previous examples. Isolation of the oily base in the usual manner and preparation of an oxalate salt yielded a product of M.P. 118-12l C. After several recrystallizations from alcohol-ether a less soluble, higher melting form of A -dehydro-Nfl-dimethyl-isomorphinan oxalate was obtained, M.P. 201-202 C. AnaIysis.--Calcd. for C H N-(COOH) C, 69.95; H, 7.33. Found: C, 69.85; H, 6.98.

Example 4 A -dehydro-l6-oxo-isomorphinan (2.0 g.) in absolute alcohol (100 ml.) was hydrogenated using platinum oxide as catalyst. The required amount of hydrogen was absorbed in about fifteen minutes at room temperature and low pressure. Evaporation of the filtered solution left a viscous oil which crystallized immediately upon trituration with methanol. After recrystallization there was obtained 1.4 g. of 16-oxo-isomorphinan, M.P. 206- 208 C.

Example 5 A solution of 1.4 g. of 16-oxo-isomorphinan in 100 m1. of purified dioxane was treated with 0.3 g. of sodium hydride. After four-five hours refluxing and stirring an excess (2 ml.) of methyl iodide was introduced and the heating resumed for an additional hour. The cooled reaction mixture was decomposed with water, the dioxane evaporated in vacuo, and the mixture extracted with chloroform. The chloroform extract was washed with water to remove sodium iodide, dried, and concentrated to dryness. A residue of N-methyl-16-oxo-isomorphinan was obtained which, on purification, melted at 117- 118 C.

Example 6 0.5 g. of N-methyl-l6-oxo-isomorphinan in 100 ml. of dioxane was reduced with hydrogen at 210 (1., 6,000 p.s.i., over a period of eight hours using 2 g. of copper chromite as catalyst. Separation of the catalyst and removal of the solvent gave a colorless oil which upon treatment with alcoholic hydrogen bromide was converted to N-methyl-isomorphinan hydrobromide, M.P. 248- 249 C. The salt was identical in melting point and rnixed melting point with authentic N-methylisomorphinan hydrobromide.

Example 7 To about two grams of A -dehydro-l6-oxo-isomorphinan dissolved in 100 ml. of dry toluene is added a dry toluene suspension of about 0.2 g. of sodium hydride, and the mixture is stirred and heated at the reflux tem perature of the solvent for a period of about two hours. To the yellow solution thus obtained is added dropwise about one milliliter of allyl bromide, and the solution is heated at reflux temperature for an additional two-hour period. The solution is cooled, treated cautiously with a small volume of water, and finally washed with water to remove precipitated sodium bromide. The organic layer is concentrated under reduced pressure to give A dehydro-N-allyl-l6-oxo-is0morphinan. Without further purification, the M-dehydro-N-allyl-l6-oxo-isomorphinan is dissolved in about 100 ml. of purified dioxane, and

the solution is heated to reflux temperature. An ether solution containing about one gram of lithium aluminum hydride is added dropwise, most of the ether is removed by distillation, and the remaining solution is heated overnight under reflux. The reaction solution is treated with a minimum amount of water thereby decomposing excess lithium aluminum hydride, the resulting mixture is filtered, and the solvent is evaporated to give a colorless oil. A solution of hydrogen bromide in ether is added to this oil to give crude A -dehydro-N-allyl-isomorphinan hydrobromide which, upon recrystallization from alcoholeth-er, gives essentially pure A -dehydro-N-allyl-isomorphinan, M.P. 2l6-218 C. (slight decomposition). Analysis.-Calcd for C H NBr (346.31) C, 65.89; H, 6.99; N, 4.04. Found: C, 65.71; H, 6.88. N, 3.93.

Example 8 A solution of about 1.4 g. of Idem-isomorphinan in ml. of purified dioxane is treated with about 0.3 g. of sodium hydride. After four to five hours of heating under reflux and stirring, about two milliliters of allyl bromide is added to the solution, and the heating resumed for an additional hour. The reaction mixture is cooled, excess sodium hydride is decomposed by the addition of water, the dioxane is evaporated under reduced pressure, and the mixture extracted with chloroform. The chloroform extract is washed with water to remove sodium bromide, dried, and evaporated to dryness to give N-allyl- 16-oxo-isomorp'hinan.

About one-half gram of N-allyl-l6-oxo-isomorphinan is dissolved in about 100 m1. of dioxane, and the solution is heated to reflux temperature. To this solution is added dropwise an ether solution containing about one-half gram of lithium aluminum hydride, most of the ether is distilled, and the remaining solution is heated overnight under reflux. A minimum volume of water is added to the reaction solution thereby decomposing excess lithium aluminum hydride, the mixture is filtered, and the solvent is distilled to give a residual oil. A solution of hydrogen bromide in other is added to the oil and the solid material thus formed is recrystallized from alcohol-ether to give substantially pure N-a-llyl-isomorphinan hydrobromide, M.P. 225 C. Analysis.-Calcd for C H NBr (348.33) C, 65.51; H, 7.53; N, 4.02. Found: C, 65.37; H, 7.62; N, 3.87.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are obvious to those skilled in the art, they are to be considered as part of this invention and are to be covered by the annexed claims.

I claim:

1. In the process of converting l6-oxo-isomorphinan compounds to the corresponding N-substituted-isomorphinan compound in which the substituent attached to the nitrogen atom is a lower aliphatic hydrocarbon radical of from one to six carbon atoms, the improvement for effectuating the rapid removal of the l6-oxo grouping with accompanying production of a high yield of the corresponding 16-desoxy derivative which comprises reacting the corresponding N-substituted -16 oxo-isomorphinan compound with an alkali metal aluminum hydride.

2. In the process of converting 16-oxo-isomorphinan to N-alkyl-isomorphinan, the step which comprises reacting N-alkyl-16-oxo-isomorphinan wherein the N-alkyl radical possesses from one to six carbon atoms with an alkali metal aluminum hydride to form said N-alkyl-isomorphinan.

3. In the process of converting A -dehydro-16-oxoisomorphinan to A -dehydro-N-alkyl-isomorphinan, the step which comprises reacting A -dehydro-Nalkyl-16-oxoisomorphinan wherein the N-alkyl radical possesses from one to six carbon atoms with an alkali metal aluminum hydride to form A -dehydro-N-alkyl-isomorphinan.

4. The process which comprises reacting A -dehydro-N- allyl-16-oxo-is0morphinan with lithium aluminum hydride to form A -dehydro-N-allyl-isomorphinan.

' 5. The process which comprises reacting aliyl iodide with 16-ox0-isomorphinan to produce N-al1y1-16-oxoisomorphinan, and reacting said N-a1ly1-16-oxo-isomorphinan with lithium aluminum hydride to form N-ailylisomorphinan.

6. The process which comprises reacting A dehydro- 16-oxo-isomorphinan with iallyl iodide to produce A6-dehydro-N-allyM6-oxo-isomorphinan, and reacting said A -dehydro-N-allyl 16 oxo-isomor-phinan with lithium aluminum hydride to form A -dehydro-N-ai-lyl-isomorphinan.

References fitted in the file of this patent UNITED STATES PATENTS Gates Oct. 9, 1956 OTHER REFERENCES Gates et al.: Journal American Chem. Soc., vol. 72,

pages 11414146 1950 Ka-rrer: Heiv. Chim. Acta., vol. 33, pages 294-7 (1950). 

1. IN THE PROCESS OF CONVERTING 16-OXO-ISOMORPHINAN COMPOUNDS TO THE CORRESPONDING N-SUBSTITUTED-ISOMORPHINAN COMPOUND IN WHICH THE SUBSTITUENT ATTACHED TO THE NITROGEN ATOM IS A LOWER ALIPHATIC HYDROCARBON RADICAL OF FROM ONE TO SIX CARBON ATOMS, THE IMPROVEMENT FOR EFFECTUATING THE RAPID REMOVAL OF THE 16-OXO GROUPING WITH ACCOMPANYING PRODUCTION OF A HIGH YIELD OF THE CORRESPONDING 16-DESOXY DERIVATIVE WHICH COMPRISES REACTING THE CORRESPONDING N-SUBSTITUTED - 16 - OXO-ISOMORPHINAN COMPOUND WITH AN ALKALI METAL ALUMINUM HYDRIDE. 